The role of neurologists in the era of cancer immunotherapy: Focus on CAR T-cell therapy and immune checkpoint inhibitors

Abstract

Cancer immunotherapy represents a novel anticancer strategy that acts directly on the immune system, promoting its activation toward cancer cells to enhance its natural ability to fight cancer. Among various treatments currently used or investigated, chimeric antigen receptors (CAR) T-cell therapy and immune checkpoint inhibitors (ICIs) have consistently proven their efficacy. These innovations are progressively improving the standard of care in cancer treatment, yet they are hampered by novel neurological adverse events, attributing to neurologists a key role in the multidisciplinary oncological team. Indeed, neurotoxicity may develop in up to 77% of patients who received CAR T-cell therapy and usually presents with encephalopathy characterized by a predominant frontal lobe dysfunction. This neurotoxicity is related to cytokine release syndrome, a systemic hyperinflammatory condition triggered by CAR T-cells. On the other hand, following treatment with ICIs, unrestrained T-cells may lead to central and peripheral neurological disorders by antigen-directed autoimmunity. Notably, biological and clinical similarities have been underlined between neurotoxicity related to CAR T-cell therapy and neurological manifestations of cytokine storms (e.g. COVID-19-related encephalopathy), as well as between a subgroup of ICI-related neurological adverse events and paraneoplastic neurological syndromes. Therefore, these cancer immunotherapy-related neurological syndromes may provide an unprecedented, perhaps transitory, opportunity to shed light on the underlying pathogenic mechanisms of a wide spectrum of neurological syndromes and to push forward our knowledge in neuroimmunology.

Brain FDG‐PET findings in chimeric antigen receptor T‐cell therapy neurotoxicity for diffuse large B‐cell lymphoma

“…In some patients, T‐cell expansion and associated cytokine production can specifically affect the central nervous system resulting in ICANS. ICANS may occur in up to one third of patients using commercially available CAR‐T therapies 1,8–13 …”

“…Pretreatment disease burden, in vivo CAR T‐cell expansion, CAR T‐cell dose, and severe CRS are considered risk factors for ICANS. Clinical features and time course of ICANS are heterogeneous and may include headache, mild cognitive impairment, language disorders, and other motor deficits, such as seizure and, potentially, global encephalopathy, possibly leading to death 8–12 . Conversely, low‐grade neurotoxicity associated with CAR T‐cell therapy is typically managed conservatively with supportive care 1 …”

“…To date, there are no specific disease‐modifying treatments. High‐grade neurotoxicity can be treated with corticosteroids to mitigate the function of CAR T cells and other bystander immune cells that are activated after CAR T‐cell infusion 1,11 . Patients’ support is also based on symptom management (especially of cerebral edema and seizures), and in case of severe (grade 3‐4) neurotoxicity, monitoring in the intensive care unit is required.…”

“…ICANS may occur in up to one third of patients using commercially available CAR-T therapies. 1,[8][9][10][11][12][13] Pretreatment disease burden, in vivo CAR T-cell expansion, CAR T-cell dose, and severe CRS are considered risk factors for ICANS.…”

“…Clinical features and time course of ICANS are heterogeneous and may include headache, mild cognitive impairment, language disorders, and other motor deficits, such as seizure and, potentially, global encephalopathy, possibly leading to death. [8][9][10][11][12] Conversely, low-grade neurotoxicity associated with CAR T-cell therapy is typically managed conservatively with supportive care. 1 The Immune-Effector Cell-Associated Encephalopathy scale, a neurotoxicity grading scale incorporating clinical symptoms, has been proposed for the evaluation of these patients.…”